Interleukin-10 (“IL-10” hereafter) is a major, anti-inflammatory cytokine, which was originally identified as a factor which inhibited cytokine production by activated TH1 lymphocytes. See Moore, et al, Annu. Rev. Immunol 19:683 (2001), incorporated by reference, for a review discussing the molecule. Following the identification of IL-10, several additional cytokines, with varying degrees of homology to IL-10 were identified. The first of these was named “mda-7”, an acronym for “melanocyte differentiation associated gene 7”, because its expression was upregulated during in vitro differentiation of a melanoma cell line. See Jiang, et al., Oncogene 11:2477 (1995). This protein exhibits 22% amino acid identity with IL-10, but it was not originally recognized as a secreted protein. Expression of mda-7 is reported to provoke irreversible growth arrest of tumors via induction of apoptosis or differentiation; however, it is not clear if this effect results from a paracrine loop that involves a classic cytokine receptor pathway, or from a cytoplasmic form of the mda-7 molecule. Recently, Schaefer, et al., J. Immunol 166:5859 (2001), identified the murine orthologue of mda-7, as a TH2-specific cytokine, and named it “IL-4 induced secreted protein,” or “FISP.” The rat counterpart, identified by Zhang, et al., J. Biol. Chem 275:24436 (2000), is referred to as “mob5”, and is expressed by intestinal epithelial cells upon ras activation. Zhang, et al. have suggested that mob5 plays a role in ras oncogene-mediated neoplasia, through an autocrine loop involving a putative, ras-inducible cell surface receptor. Soo, et al., J. Cell Biochem. 74:1 (1999), have cloned the gene for mob 5and determined that it is overexpressed in the skin during wound healing.
Both the IL-10 and mda-7 genes have been mapped to chromosome 1q31–32, which is a region where two other, IL-10 related genes are found, i.e., “IL-19” and “IL-20.” IL-19 is expressed by LPS activated peripheral blood mononuclear cells, as reported by Gallagher, et al., Genes Immun 1:442 (2000). As for IL-20, its biological activities have been studied by using transgenic mice which overexpress the cytokine, where the gene is under the control of various promoters. Such mice, as reported by Blumberg, et al., Cell 104:9 (2001), are characterized by neonatal lethality, and skin abnormalities, including aberrant epidermal differentiation, which is reminiscent of psoriasis lesions in humans. Blumberg, et al., have described the IL-20 receptor complex as a heterodimer of two orphan class II cytokine receptor subunits. Specifically, “CRF2–8,” for which the name “IL-20Rα” has been suggested, and “DIRS1”, for which “IL-20Rβ” has been suggested.
Two other genes for IL-10 homologous cytokines, i.e., “AK155” and “IL-22” are located on human chromosome 12q15, near the IFN-γ gene. AK155 is a novel cytokine which is constitutively expressed in T lymphocytes. It was found to be strongly upregulated by Herpes virus saimiri transformation of T lymphocytes. See Knappe, et al., J. Virol 74:3381 (2000), incorporated by reference. The authors suggest that AK155 plays a role in autocrine growth stimulation leading to spontaneous proliferation of T cells. The IL-22 molecule was originally described as an IL-9 inducible gene, and was referred to as “IL-TIF,” for “IL-10 related T cell derived inducible factor.” See Dumoutier, et al., J. Immunol 164:1814 (2000), incorporated by reference, as well as PCT Application WO 00/24758, incorporated by reference and the U.S. priority applications referred to therein. The activities of IL-22 include the induction of the acute phase response, especially in hepatocytes and they are mediated through a heterodimeric receptor which consists of the CRF2–9/IL-22R subunit, and the β chain of the IL-10 receptor. See, e.g., Dumoutier, et al., Proc. Natl., Acad. Sci USA 97:10144 (2000); Kotenko, et al., J. Biol. Chem 276:2725 (2000); Xie, et al., J. Biol. Chem 275:31335 (2000), all of which are incorporated by reference. Induction of the acute phase response is associated with inflammation, allergic responses, and cancer, thus suggesting that modulation of the interaction between IL-9 and IL-22 can lead to alleviation of these conditions. In addition to its cellular receptor, IL-22 binds to a secreted member of the class II cytokine receptor family, referred to as “IL-22BP,” or “IL-22 binding protein,” which acts as a natural IL-22 antagonist. See Dumoutier, et al., J. Immunol 166:7090 (2001), Kotenko, et al., J. Immunol 166:7096 (2001), incorporated by reference. The 12q region, particularly the interferon γ region, has been linked to or associated with a variety of autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, types I and II diabetes mellitus, allergies and asthma. This suggests that AK155 and/or IL-22 in view of the location of the genes encoding these cytokines, may be involved in one or more of these, or other, autoimmune diseases.
It will be understood from the above, that there are two classes of cytokine receptors, i.e., class I and class II. Within the class I cytokine receptors, sharing of receptor subunits is a well recognized phenomenon. Subfamilies have been defined as a result of this phenomenon, including the gp130 and IL-2R families. In the case of class II receptors, however, the only example of a shared receptor up to now has been the IL-10Rβ chain, which is involved in both IL-10 and IL-22 signaling. See Dumoutier, et al., Proc. Natl. Acad. Sci USA 97:10144 (2000); Kotenko, et al., J. Biol. Chem 276:2725 (2000); Xie, et al., J. Biol. Chem 275:31335 (2000) U.S. patent application Ser. No. 09/915,735, filed Jul. 26, 2001 and incorporated by reference herein, describes members of the Class II cytokine receptor family, and a newly observed complex of two of these, i.e., IL-20Rβ and, IL-22R. It is of interest to determine the role of different class II cytokine receptors in the functions of different cytokines.
The disclosure which follows discusses the isolation and cloning of a new member of this family, referred to as “LICR-2.” A ligand for this receptor has been identified as AK155. These features of the invention, as well as others, are described in the Detailed Description which follows.